Skip to main content

Overdose of Atypical Antipsychotics

Clinical Presentation, Mechanisms of Toxicity and Management

CNS Drugs volume 26, pages 601–611 (2012)Cite this article

An Erratum to this article was published on 01 September 2012

Abstract

Historically, treatment for schizophrenia focused on sedation. The advent of the typical antipsychotics resulted in treatment aimed specifically at the underlying disease, but these agents were associated with numerous adverse effects, and were not particularly effective at treatment of the negative symptoms of schizophrenia. As a result, numerous atypical agents have been developed over the past 2 decades, including several agents within the past 5 years.

Overdose of antipsychotics remains quite common in Western society. In 2010, poison control centres in the US received nearly 43 000 calls related to atypical antipsychotics alone. Due to underreporting, the true incidence of overdose with atypical antipsychotics is likely much greater. Following overdose of an atypical antipsychotic, the clinical effects observed, such as CNS depression, tachycardia and orthostasis are largely predictable based on the unique receptor binding profile of the agent. This article, which focuses on the atypical antipsychotics commonly used in the treatment of schizophrenia, discusses the features commonly encountered in overdose. Specifically, agents that result in QT prolongation and the corresponding potential for torsades de pointes, as well as unique features encountered with the various medications are discussed. The diagnosis of this overdose is largely based on history. Routine use of drug screens is unlikely to be beneficial. The primary goal of management is aggressive supportive care. Patients with significant CNS depression with associated loss of airway reflexes and respiratory failure need advanced airway management. Hypotension should be treated first with intravenous fluids, with the use of direct acting vasopressors reserved for persistent hypotension. Benzodiazepines should be used for seizures, with barbiturates used for refractory seizures. Intravenous magnesium can be administered for patients with a corrected QT interval exceeding 500 milliseconds.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

£ 34.95

Price includes VAT (United Kingdom)
Tax calculation will be finalised during checkout.

Table I

References

  1. Awad AG, Voruganti LN. Impact of atypical antipsychotics on quality of life in patients with schizophrenia. CNS Drugs 2004; 18:877–93

    PubMed  Article  CAS  Google Scholar 

  2. Burns MJ. The pharmacology and toxicology of atypical antipsychotic agents. Clin Toxicol 2001; 39: 1–14

    Article  CAS  Google Scholar 

  3. Meltzer HY, Li Z, Kaneda Y, et al. Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsy-chopharmacol Biol Psychiatry 2003; 27: 1159–72

    Article  CAS  Google Scholar 

  4. Moller HJ. Definition, psychopharmacological basis and clinical evaluation of novel/atypical neuroleptics: meth-odlogical issues and clinical consequences. World J Biol Psychiatry 2000; 1: 75–91

    PubMed  Article  CAS  Google Scholar 

  5. Ross CA, Margolis RL, Reading SA, et al. Neurobiology of schizophrenia. Neuron 2006; 52: 139–53

    PubMed  Article  CAS  Google Scholar 

  6. Raggi MA, Mandrioli R, Sabbioni C, et al. Atypical antipsychotics: pharmacokinetics, therapeutic drug monitoring, and pharmacological interactions. Curr Med Chem 2004; 11: 279–96

    PubMed  Article  CAS  Google Scholar 

  7. Meltzer HY, Massey BW. The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol 2011; 11: 59–67

    PubMed  Article  CAS  Google Scholar 

  8. Meyer JM. Pharmacotherapy of psychosis and mania. In: Brunton LL, editor. Goodman and Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw Hill, 2011; 417–55

    Google Scholar 

  9. Ishibashi T, Horisawa T, Tokuda K, et al. Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5 HT1A receptor activity. J Pharmacol Exp Ther 2010; 334: 171–81

    PubMed  Article  CAS  Google Scholar 

  10. Jibson MD, Tandon R. New atypical antipsychotic medications. J Psychiatr Res 1998; 32: 215–8

    PubMed  Article  CAS  Google Scholar 

  11. Blin O. A comparative review of new antipsychotics. Can J Psychiatry 1999; 44: 235–44

    PubMed  CAS  Google Scholar 

  12. Cheslik TA, Erramouspe J. Extrapyramidal symptoms following accidental ingestion of risperidone in a child. Ann Pharmacother 1996; 30: 360–3

    PubMed  CAS  Google Scholar 

  13. Richelson E. Receptor pharmacology of neuroleptics: relation to clinical effects. J Clin Psychiatry 1999; 60 Suppl. 10: 5–14

    PubMed  CAS  Google Scholar 

  14. Borison RL. Recent advances in the pharmacotherapy of schizophrenia. Harvard Rev Psychiatry 1997; 4: 255–71

    Article  CAS  Google Scholar 

  15. Hoiberg MP, Nielsen B. Antipsychotic treatment and extrapyramidal symptoms amongst schizophrenic inpatients. Nord J Psychiatry 2006; 60: 207–12

    PubMed  Article  CAS  Google Scholar 

  16. Haddad PM, Sharma SG. Adverse effects of atypical antipsychotics: differential risk and clinical implications. CNS Drugs 2007; 21: 911–36

    PubMed  Article  CAS  Google Scholar 

  17. Levine M, Brooks DE, Truitt CA, et al. Toxicology in the ICU, part 1: general overview and approach to treatment. Chest 2011; 140:795–806

    PubMed  Article  CAS  Google Scholar 

  18. Grace AA, Bunney BS, Moore H, et al. Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs. Trends Neurosci 1997; 20: 31–7

    PubMed  Article  CAS  Google Scholar 

  19. Kapur S, Remington G. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry 1996; 153:466–76

    PubMed  CAS  Google Scholar 

  20. Solian prescribing information [online]. Available from URL: http://www.sanofi.com.au/products/aus_pi_solian.pdf [Accessed 2012 Jan 30]

  21. Merck and Co., Inc. Saphris prescribing information [online]. Available from URL: http://www.spfiles.com/pisaphrisv1.pdf [Accessed 2012 Jan 30]

  22. Bristol Myers-Squibb. Aripiprazole prescribing information [online]. Available from URL: http://www.abilify.com/pdf/pi.aspx [Accessed 2012 Jan 30]

  23. Novartis Pharmaceuticals Corporation. Clozapine prescribing information [online]. Available from URL: http://www.pharma.us.novartis.com/product/pi/pdf/Clozaril.pdf [Accessed 2012 Jan 30]

  24. Arif SA, Mitchell MM. Iloperidone: a new drug for the treatment of schizophrenia. Am J Health Syst Pharm 2011; 68: 301–8

    PubMed  Article  CAS  Google Scholar 

  25. Sunovion Pharmaceuticals Inc. Lurasidone prescribing information [online]. Available from URL: http://www.latuda.com/LatudaPrescribingInformation.pdf [Accessed 2012 Jan 30]

  26. Astra Zenica. Quetiapine prescribing information [online]. Available from URL: http://www1.astrazeneca-us.com/pi/Seroquel.pdf [Accessed 2012 Jan 30]

  27. Janssen Pharmaceuticals Inc. Risperidone prescribing information [online]. Available from URL: http://www.risperdal.com/prescribing.html [Accessed 2012 Jan 30]

  28. Lilly USA LLC. Olanzapine prescribing Information [online]. Available from URL: http://pi.lilly.com/us/zyprexa-pi.pdf [Accessed 2012 Jan 30]

  29. Janssen Pharmaceuticals Inc. Paliperidone prescribing information [online]. Available from URL: http://www.invega.com/prescribing-information [Accessed 2012 Jan 30]

  30. Pfizer Inc. Ziprasidone prescribing information [online]. Available from URL: http://labeling.pfizer.com/ShowLabeling.aspx?id=584 [Accessed 2012 Jan 30]

  31. Keck Jr PE, McElroy SL. Clinical pharmacodynamics and pharmacokinetics of antimanic and mood-stabilizing medications. J Clin Psychiatry 2002; 63 Suppl. 4: 3–11

    PubMed  CAS  Google Scholar 

  32. Yang PL, Plosker GL. Paliperidone extended release. CNS Drugs 2007; 21: 417–25

    PubMed  Article  CAS  Google Scholar 

  33. Dubois D. Toxicology and overdose of atypical anti-psychotic medications in children: does newer necessarily mean safer. Curr Opin Pediatr 2005; 17: 227–33

    PubMed  Article  Google Scholar 

  34. Wadworth AN, Heel RC. Remoxipride: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in schizophrenia. Drugs 1990; 40: 863–79

    PubMed  Article  CAS  Google Scholar 

  35. Wiesel FA, Alfredsson G, Ehrnebo M, et al. The pharma-cokinetics of intravenous and oral sulpiride in healthy human subjects. Eur J Clin Pharmacol 1980; 17: 385–91

    PubMed  Article  CAS  Google Scholar 

  36. Rosenzweig P, Canal M, Patat A, et al. A review of the pharmacokinetics, tolerability, and pharmacodynamics of amisulpride in healthy volunteers. Hum Psychopharmacol 2002; 17: 1–13

    PubMed  Article  CAS  Google Scholar 

  37. Micromedex. Version 2.0 [online]. Available from URL: http://www.thomsonhc.com/micromedex2/librarian [Accessed 2011 Oct 17]

  38. Bronstein AC, Spyker DA, Cantilena Jr LR, et al. 2010 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th annual report. Clin Toxicol (Phila) 2011; 49: 910–41

    Article  Google Scholar 

  39. Isbister GK, Balit CR, Kilham HA. Antipsychotic poisoning in young children: a systematic review. Drug Saf 2005; 28: 1029–44

    PubMed  Article  CAS  Google Scholar 

  40. Balit CR, Isbister GK, Hackett LP, et al. Quetiapine poisoning: a case series. Ann Emerg Med 2003; 42: 751–8

    PubMed  Article  Google Scholar 

  41. Gresham C, Ruha AM. Respiratory failure following isolated ziprasidone ingestion in a toddler. J Med Toxicol 2010;6:41–3

    PubMed  Article  CAS  Google Scholar 

  42. O’Malley GF, Seifert S, Heard et al. Olanzapine overdose mimicking opioid intoxication. Ann Emerg Med 1999; 34: 279–81

    PubMed  Article  Google Scholar 

  43. Palenzona S, Meier PK, Kupferschmidt H, et al. The clinical picture of olanzapine poisoning with special reference to fluctuating mental status. J Toxicol Clin Toxicol 2004; 42: 27–32

    PubMed  Article  CAS  Google Scholar 

  44. Page CB, Calver LA, Isbister GK. Risperidone overdose causes extrapyramidal effects but not cardiac toxicity. J Clin Psychopharmacol 2010; 30: 387–90

    PubMed  Article  CAS  Google Scholar 

  45. Lapid MI, Cunningham JL, Hugo Z, et al. Acute dystonia associated with paliperidone overdose. Psychosomatics 2011;52:291–4

    PubMed  Article  Google Scholar 

  46. Theisen FM, Grabarkiewicz J, Fegbeutel C, et al. Olanzapine overdose in children and adolescents: two case reports and a review of the literature. J Child Adolesc Psychopharmacol 2005; 15: 986–95

    PubMed  Article  Google Scholar 

  47. Cohen LG, Fatalo A, Thompson BT, et al. Olanzapine overdose with serum concentrations. Ann Emerg Med 1999; 34: 275–8

    PubMed  Article  CAS  Google Scholar 

  48. Khan KH, Tham TC. Neuroleptic malignant syndrome induced by quetiapine overdose. Br J Hosp Med (Lond) 2008; 69: 171

    CAS  Google Scholar 

  49. Isbister GK, Balit CR, Macleod D, et al. Amisulpride overdose is frequently associated with QT prolongation and torsades de pointes. J Clin Psychopharmacol 2010; 30: 391–5

    PubMed  Article  Google Scholar 

  50. Zareba W, Lin DA. Antipsychotic drugs and QT interval prolongation. Psychiatr Q 2003; 74: 291–306

    PubMed  Article  Google Scholar 

  51. Tan HH, Hoppe J, Heard A systematic review of cardiovascular effects after atypical antipsychotic medication overdose. Am J Emerg Med 2009; 27: 607–16

    PubMed  Article  Google Scholar 

  52. Moller HJ. Amisulpride: limbic specificity and the mechanism of antipsychotic atypicality. Prog Neuropsycho-pharmacol Biol Psychiatry 2003; 27: 1101–11

    Article  CAS  Google Scholar 

  53. Green B. Focus on amisulpride. Curr Med Res Opin 2002; 18: 113–7

    PubMed  Article  CAS  Google Scholar 

  54. Isbister GK, Murray L, John S, et al. Amisulpride deliberate self-poisoning causing severe cardiac toxicity include QT prolongation and torsades de pointes. Med J Aust 2006; 184: 354–6

    PubMed  Google Scholar 

  55. Joy JP, Coulter CV, Duffull SB, et al. Prediction of torsades de pointes from the QT interval: analysis of a case series of amisulpride overdoses. Clin Pharmacol Ther 2011; 90: 243–5

    PubMed  Article  CAS  Google Scholar 

  56. Wang YC, Yang CC, Bai YM, et al. Heart rate variability in schizophrenic patients switched from typical antipsychotic agents to amisulpride and olanzapine. Neuropsychobiology 2008; 57: 200–5

    PubMed  Article  CAS  Google Scholar 

  57. Tracqui A, Mutter-Schmidt C, Kintz P, et al. Amisulpride poisoning: a report on two cases. Hum Exp Toxicol 1995; 14: 294–8

    PubMed  Article  CAS  Google Scholar 

  58. Ventimiglia J, Kalali AH, Citrome L. A review of new atypical antipsychotic launches in the United States. Psychiatry (Edgemeont) 2010; 7: 13–5

    Google Scholar 

  59. Weber J, McCormack PL. Asenapine. CNS Drugs 2009; 23: 781–92

    PubMed  Article  CAS  Google Scholar 

  60. Balaraman R, Gandhi H. Asenapine, a new sublingual atypical antipsychotic. J Pharmacol Pharmacother 2010; 1: 60–1

    PubMed  Article  CAS  Google Scholar 

  61. Lofton AL, Klein-Schwartz W. Atypical experience: a case series of pediatric aripiprazole exposures. Clin Toxicol (Phila) 2005; 43: 151–3

    Google Scholar 

  62. Young MC, Shah N, Cantrell FL, et al. Risk assessment of isolated aripiprazole exposures and toxicities: a retrospective study. Clin Toxicol 2009; 47: 580–3

    Article  CAS  Google Scholar 

  63. Seifert SA, Schwartz MD, Thomas JD. Aripiprazole (abilify) overdose in a child. Clin Toxicol (Phila) 2005; 43: 193–5

    CAS  Google Scholar 

  64. Melhem S, Katz Jameson A. Prolonged toxicity in a 2-year-old after accidental ingestion of aripiprazole. Pediatr Emerg Care 2009; 25: 105–6

    PubMed  Article  Google Scholar 

  65. Goodnick PJ, Jerry J, Parra F. Psychotropic drugs and the ECG: focus on the QT interval. Expert Opin Pharmacother 2002; 3: 479–98

    PubMed  Article  CAS  Google Scholar 

  66. Hippius H. A historical prospective of clozapine. J Clin Psychiatry 1999; 60 Suppl 12: 22–3

    PubMed  Google Scholar 

  67. Reith D, Montelone JP, Whyte IM, et al. Features and toxicokinetics of clozapine in overdose. Ther Drug Monit 1998; 20: 92–7

    PubMed  Article  CAS  Google Scholar 

  68. Bird AM, Smith TL, Walton AE. Current treatment strategies for clozapine-induced sialorrhea. Ann Pharmacother 2011;45:667–75

    PubMed  Article  CAS  Google Scholar 

  69. Thomas L, Pollak PT. Delayed recovery associated with persistent serum concentrations after clozapine overdose. J Emerg Med 2003; 25: 61–6

    PubMed  Article  Google Scholar 

  70. Warner B, Hoffmann P. Investigation of the potential of clozapine to cause torsade de pointes. Adverse Drug React Toxicol Rev 2002; 21: 189–203

    PubMed  CAS  Google Scholar 

  71. Layland JJ, Liew D, Prior DL. Clozapine-induced cardio-toxicity: a clinical update. Med J Aust 2009; 190: 190–2

    PubMed  Google Scholar 

  72. Meeker JE, Herrmann PW, Som CW. Clozapine tissue concentrations following an apparent suicidal overdose of clozaril. J Anal Toxicol 1992; 16: 54–6

    PubMed  CAS  Google Scholar 

  73. Scott LJ. Ioperidone in schizophrenia. CNS Drugs 2009; 23: 867–80

    PubMed  Article  CAS  Google Scholar 

  74. Kalkman HO, Feuerbach D, Lotscher E, et al. Functional characterization of the novel antipsychotic iloperidone at human D2, D3, α2c, 5-HT6, and 5-HT1A receptors. Life Sci 2003; 73: 1151–9

    PubMed  Article  CAS  Google Scholar 

  75. Citrome L. Lurasidone for schizophrenia: a brief review of a new second-generation antipsychotic. Clin Schizophr Relat Psychoses 2011; 4: 251–7

    PubMed  Article  Google Scholar 

  76. Citrome L. Lurasidone for schizophrenia: a review of the efficacy and safety profile for this newly approved second-generation antipsychotic. Int J Clin Pract 2011; 65: 189–210

    PubMed  Article  CAS  Google Scholar 

  77. Morgan M, Hackett LP, Isbister GK. Olanzapine overdose: a case series of analytically confirmed cases. Int Clin Psy-chopharmacol 2007; 22: 183–6

    Article  Google Scholar 

  78. Waring WS, Wrate J, Bateman DN. Olanzapine overdose is associated with acute muscle injury. Hum Exp Toxicol 2006; 25: 735–40

    PubMed  Article  CAS  Google Scholar 

  79. Tse GH, Warner MH, Waring WS. Prolonged toxicity after massive olanzapine overdose: two cases with confirmatory laboratory data. J Toxicol Sci 2008; 33: 363–5

    PubMed  Article  CAS  Google Scholar 

  80. Ngo A, Ciranni M, Olson KR. Acute quetiapine overdose in adults: a 5-year retrospective case series. Ann Emerg Med 2008; 52: 541–7

    PubMed  Article  Google Scholar 

  81. Isbister GK, Duffull SB. Quetiapine overdose: predicting intubation, duration of ventilation, cardiac monitoring, and the effect of activated charcoal. Int Clin Psycho-pharmacol 2009; 24: 174–80

    Article  Google Scholar 

  82. Hunfeld NG, Westerman EM, Boswijk DJ, et al. Quetiapine in overdosage: A clinical and pharmacokinetic analysis of 14 cases. Ther Drug Monit 2006; 28: 185–9

    PubMed  Article  CAS  Google Scholar 

  83. Bodmer M, Burkard T, Kummer O, et al. Pharmacokinetics and pharmacodynamics of quetiapine in a patient with a massive overdose. Ther Drug Monit 2008; 30: 553–6

    PubMed  Article  CAS  Google Scholar 

  84. de Leon J, Wynn G, Sandson NB. The pharmacokinetics of paliperidone versus risperidone. Psychosomatics 2010; 51: 80–8

    PubMed  Article  Google Scholar 

  85. Levine M, LoVecchio F, Tafoya P, et al. Paliperidone overdose with delayed onset of toxicity. Ann Emerg Med 2011; 58: 80–2

    PubMed  Article  Google Scholar 

  86. LoVecchio F, Watts D, Eckholdt P. Three-year experience with ziprasidone exposures. Am J Emerg Med 2005; 23: 586–7

    PubMed  Article  Google Scholar 

  87. Klein-Schwartz W, Lofton AL, Benson BE, et al. Prospective observational multi-poison center study of ziprasidone exposures. Clin Toxicol 2007; 45: 782–6

    Article  CAS  Google Scholar 

  88. Alipour A, Cruz R, Lott RS. Torsades de pointes after ziprasidone overdose with coingestants. J Clin Psycho-pharmacol 2010; 30: 76–7

    Article  Google Scholar 

  89. Manini AF, Raspberry D, Hoffman RS, et al. QT prolongation and torsadess de pointes following overdose of ziprasidone and amantadine. J Med Toxicol 2007; 3: 178–81

    PubMed  Article  Google Scholar 

  90. Gupta A, Lawrence AT, Krishnan K, et al. Current concepts in the mechanisms and management of drug-induced QT prolongation and torsades de pointes. Am Heart J 2007; 153: 891–9

    PubMed  Article  Google Scholar 

  91. White CM, Xie J, Chow MS, et al. Prophylactic magnesium to decrease the arrhythmogenic potential of class III antiarrhythmic agents in a rabbit model. Pharmacotherapy 1999; 19: 635–40

    PubMed  Article  CAS  Google Scholar 

  92. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart 2003; 89: 1363–72

    PubMed  Article  CAS  Google Scholar 

  93. Rhyee SH, Pedapati EV, Thompson J. Prolonged delirium after quetiapine overdose. Pediatr Emerg Care 2010; 26: 754–6

    PubMed  Article  Google Scholar 

  94. Sartorius A, Hewer W, Zink M, et al. High-dose clozapine intoxication. J Clin Psychopharmacol 2002; 22: 91–2

    PubMed  Article  Google Scholar 

  95. Howland MA. Antidotes in Depth (A12): Physostigmine Salicylate. In: Howland MA, editor. Goldfrank’s Toxicologic Emergencies. 9th ed. New York: McGraw-Hill, 2011

    Google Scholar 

Download references

Acknowledgements

There are no potential or actual conflicts of interest to disclose. No funding was provided for the preparation of this manuscript.

Author information

Affiliations

  1. Section of Medical Toxicology, Department of Emergency Medicine, University of Southern California, 1200 North State Street, #1011, Los Angeles, California, CA 90033, USA

    Michael Levine MD

  2. Department of Medical Toxicology, Banner Good Samaritan Medical Center, Phoenix, Azusa, USA

    Michael Levine MD & Anne-Michelle Ruha

Authors
  1. Michael Levine MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anne-Michelle Ruha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Levine MD.

Additional information

An erratum to this article is available at http://dx.doi.org/10.2165/11630370-000000000-00000.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Levine, M., Ruha, AM. Overdose of Atypical Antipsychotics. CNS Drugs 26, 601–611 (2012). https://doi.org/10.2165/11631640-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11631640-000000000-00000

Keywords

  • Clozapine
  • Olanzapine
  • Orthostatic Hypotension
  • Aripiprazole
  • Atypical Antipsychotic